Phosphodiesterase 2 inhibitor Hcyb1 reverses corticosterone-induced neurotoxicity and depression-like behavior
- Psychopharmacology (Berl). 2020 Nov;237(11):3215-3224. doi: 10.1007/s00213-019-05401-1.
- 1. School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China.
- 2. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY, 14214, USA.
- 3. School of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, Zhejiang Province, China.
- 4. Department of Neurology, The People's Hospital of Yichun City, Yichun, Jiangxi Province, China.
- 5. Department of Neurosurgery, The People's Hospital of Yichun City, Yichun, Jiangxi Province, China.
- 6. Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA.
- 7. Department of Behavioral Medicine & Psychiatry, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA.
- 8. Department of Physiology & Pharmacology, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA.
- 9. Department of Neuroscience, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA.
- 10. Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, NC, USA.
- 11. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, USA.
- 12. School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China. [email protected].
- 13. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY, 14214, USA. [email protected].
Rationale: Currently available PDE2 inhibitors have poor brain penetration that limits their therapeutic utility in the treatment of depression. Hcyb1 is a novel selective PDE2 Inhibitor that was introduced more lipophilic groups with polar functionality to the scaffold pyrazolopyrimidinone to improve the blood-brain barrier (BBB) penetration. Our previous study suggested that Hcyb1 increased the neuronal cell viability and exhibited antidepressant-like effects, which were parallel to the currently available PDE2 Inhibitor Bay 60-7550.
Objectives: The present study investigated whether Hcyb1 protected HT-22 cells against corticosterone-induced neurotoxicity and produced antidepressant-like effects in behavioral tests in stressed mice.
Methods: The neuroprotective effects of Hcyb1 against corticosterone-induced cell lesion were examined by cell viability (MTS) assay. The enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis were used to determine the levels of cAMP or cGMP and expression of pCREB or BDNF, respectively, in the corticosterone-treated HT-22 cells. The antidepressant-like effects of Hcyb1 were determined in the tail suspension and novelty suppressed feeding tests in stressed mice.
Results: In the cell-based assay, Hcyb1 significantly increased cell viability of HT-22 cells against corticosterone-induced neurotoxicity in a time- and dose-dependent manner. Hcyb1 also rescued corticosterone-induced decreases in both cGMP and cAMP levels, pCREB/CREB and BDNF expression. These protective effects of Hcyb1 were prevented by pretreatment with either the PKA Inhibitor H89 or the PKG Inhibitor KT5823. Moreover, Hcyb1 reversed acute stress-induced increases in immobility time and the latency to feed in the tail suspension and novelty suppressed feeding tests, respectively, which were prevented by pretreatment with H89 or KT5823.
Conclusion: These findings provide evidence that the neuroprotective effects of Hcyb1 are mediated by PDE2-dependent cAMP/cGMP signaling.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: Phosphodiesterase (PDE)Research Areas: Neurological Disease